Protective effect of HIF-1α against hippocampal apoptosis and cognitive dysfunction in an experimental rat model of subarachnoid hemorrhage

Abstract

Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia and has been proposed as a potent therapeutic target for cerebral ischemia. However, research on the expression and effects of HIF-1α in subarachnoid hemorrhage (SAH) is limited. The aim of the present study was to investigate the expression of HIF-1α in the hippocampus and its possible protective effect against hippocampal apoptosis and cognitive dysfunction in a rat model of SAH. Seventy-two Sprague-Dawley (SD) rats were randomly divided into the sham group, the SAH+vehicle group, and the SAH+YC-1 group. Immunohistochemical staining and western blotting analyses revealed that the expression of HIF-1α and its downstream effectors, vascular endothelial growth factor (VEGF), erythropoietin (EPO), and glucose transporter 1 (GLUT1), increased in the hippocampus 48h after the induction of SAH. YC-1 blocked this upregulation. The number of active caspase-3-positive cells and the expression of active caspase-3 in the hippocampus significantly increased in the YC-1 group relative to the vehicle group. A cell death assay further revealed that DNA fragmentation was significantly increased at 48h in the YC-1 group compared with the vehicle group. In Morris water maze (MWM) tests, the YC-1 group showed increased escape latency times and distances as well as reduced time spent and distance traveled in the target quadrant. These results indicate that hippocampal apoptosis increased and cognitive function deteriorated when HIF-1α was inhibited, suggesting that HIF-1α has a neuroprotective effect in SAH and may represent an effective therapeutic target.